A new mucosal adjuvant for augmenting influenza vaccines in elderly

一种用于增强老年人流感疫苗接种效果的新型粘膜佐剂

• 批准号: 10304406
• 负责人: Mei X Wu
• 金额: $ 48.27万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-24 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10304406
• 关键词: Address; Adjuvant; Adjuvanticity; Age; Aging; Agonist; Air; Alveolar Macrophages; Antigen Targeting; Antigen-Presenting Cells; Attenuated; Biological Response Modifiers; Biomimetics; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; COVID-19; COVID-19 pandemic; Cause of Death; Cell Aging; Cells; Cellular Immunity; Cessation of life; Clinical; Cyclic GMP; Cytosol; Defect; Dendritic Cells; Disease; Distant; Effectiveness; Elderly; Encapsulated; Endocytosis; Engineering; Epithelial Attachment; Epithelial Cells; Excision; Face; Ferrets; Gene Activation; Genes; H1N1 vaccine; Health; Healthcare Systems; Hospitalization; Humoral Immunities; ITGAM gene; Immune; Immune response; Immune system; Immunity; Immunization; Immunization Programs; Infection; Inflammaging; Inflammation; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Influenza A Virus, H7N9 Subtype; Influenza vaccination; Inhalation; Interferons; Invaded; Learning; Liposomes; Longevity; Lung; Mediating; Medical; Membrane; Memory; Middle East Respiratory Syndrome; Modeling; Monitor; Mucous Membrane; Mus; Names; Nature; Organ; Phospholipase A2; Play; Population; Predisposition; Production; Public Health; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Respiratory System; Role; Science; Severe Acute Respiratory Syndrome; Single Nucleotide Polymorphism; Structure of parenchyma of lung; T cell response; T memory cell; T-Lymphocyte; Tissues; Tsunami; Vaccination; Vaccines; Viral Respiratory Tract Infection; Viral Vaccines; Virus; Virus Diseases; aged; aging population; alveolar epithelium; base; cost; flu; immunopathology; improved; influenza virus vaccine; interest; memory CD4 T lymphocyte; mortality; novel; particle; prevent; recruit; respiratory; response; universal influenza vaccine; vaccination strategy; young adult

Abstract This proposal is to investigate a newly developed mucosal adjuvant for its effectiveness in bolstering influenza (flu) vaccines in the elderly. Current flu vaccines are inefficacious in the elderly owing to the aged immune system and their poor stimulation of cell-mediated immunity (CMI). A powerful adjuvant capable of stimulating both humoral and cell immune responses in the elderly should greatly augment existing flu vaccines, better safeguarding this aging and growing population. We recently engineered a powerful mucosal adjuvant by encapsulating a natural STING agonist with pulmonary surfactant (PS)- biomimetic liposomes, named PS-GAMP, based on recent findings that activation of STING, the stimulator of IFN genes, can vigorously stimulate CMI and humoral immunity. PS-GAMP alongside inactivated H1N1 vaccine induced a wide spectrum of cross-protection against distant H1N1 and heterosubtypic H3N2, rgH5N1, and H7N9 viruses as early as 2 days after a single immunization. The cross-protection lasted for at least 6 months, concurrent with durable lung tissue resident memory (TRM) CD8+ T cells in young adult mice. We will extend the study to aged mice in this proposal and determine whether strong CD8+ T-cells (and perhaps CD4+ T cells as well) can be quickly induced by PS-GAMP/flu vaccine in aged mice. We will monitor a longevity of the heterosubtypic immunity, humoral immune responses, and lung TRM CD8+ and CD4+ memory T cells as mice age. Because the vaccination does not involve any replicating vaccine, pre-exiting immunity should have little effect on the efficacy of PS- GAMP/flu vaccination, which will be investigated to demonstrate significant advantages of the vaccine over live-attenuated intranasal flu vaccine that is ineffective in the elderly. Secondly, distinguished from most prominent adjuvants primarily targeting antigen-presenting cells (APCs) or professional immune cells, PS-GAMP activates both alveolar epithelial cells (AEC) and APCs. It would be interested to learn whether PS-GAMP-mediated AEC activation can offset the defects of aged APCs, eliciting strong heterosubtypic immunity in aged mice. The pivotal role for AEC will be also substantiated in ferret model. Aim 3 will investigate whether PS-GAMP/flu vaccination can be further improved in aged mice by suppressing inflammaging and/or removing senescence cells. Moreover, a novel, much more potent, and pan-STING agonist will be explored to enhance PS-GAMP’s adjuvanticity and strengthen its clinical potential. The study, if successful, would have significant impact on the overall health and quality of the aged population not only for influenza but also for other respiratory viral infections like Covid-19.

抽象的 该提案旨在研究一种新开发的粘膜佐剂在支持方面的有效性 老年人接种流感疫苗。目前的流感疫苗对老年人无效，原因是 免疫系统老化及其对细胞介导免疫（CMI）的刺激较差。强力佐剂 能够刺激老年人的体液和细胞免疫反应，应该会大大增强 现有的流感疫苗可以更好地保护老龄化和不断增长的人口。我们最近设计了一个 通过将天然 STING 激动剂与肺表面活性剂 (PS) 封装在一起，形成强大的粘膜佐剂 - 仿生脂质体，命名为 PS-GAMP，基于最近的发现，即 STING 的激活， IFN基因刺激剂，可强力刺激CMI和体液免疫。 PS-GAMP 并列 灭活 H1N1 疫苗可诱导针对远距离 H1N1 流感的广谱交叉保护， 最早在单次免疫后 2 天发现异亚型 H3N2、rgH5N1 和 H7N9 病毒。这 交叉保护持续至少 6 个月，同时具有持久的肺组织驻留记忆 (TRM) 年轻成年小鼠的 CD8+ T 细胞。我们将在本提案中将研究扩展到老年小鼠并确定 PS-GAMP/flu 是否可以快速诱导强 CD8+ T 细胞（也许还有 CD4+ T 细胞） 老年小鼠疫苗。我们将监测异亚型免疫、体液免疫的寿命 随着小鼠年龄的增长，反应以及肺 TRM CD8+ 和 CD4+ 记忆 T 细胞。因为疫苗接种会 不涉及任何复制疫苗，预退出免疫对 PS- 的功效影响不大 GAMP/流感疫苗接种，将进行研究以证明疫苗的显着优势 过度使用对老年人无效的鼻内流感减毒活疫苗。其次，区别于 主要针对抗原呈递细胞 (APC) 或专业免疫的最著名佐剂 细胞中，PS-GAMP 可激活肺泡上皮细胞 (AEC) 和 APC。会有兴趣学习一下 PS-GAMP介导的AEC激活是否可以抵消老化APC的缺陷，从而引发强烈的 老年小鼠的异亚型免疫。 AEC 的关键作用也将在雪貂模型中得到证实。 目标 3 将研究是否可以通过以下方法进一步改善老年小鼠的 PS-GAMP/流感疫苗接种： 抑制炎症和/或去除衰老细胞。此外，一部小说，更有力， 将探索泛STING激动剂以增强PS-GAMP的佐剂作用并加强其临床 潜在的。该研究如果成功，将对整体健康和质量产生重大影响 老年人不仅感染流感，还感染 Covid-19 等其他呼吸道病毒感染。